PROJECT SUMMARY/ABSTRACT Osteogenesis imperfecta (OI) is the most frequent heritable bone fragility disorder in children and is most commonly caused by genetic mutations affecting type I collagen production, which is the primary protein of bones. OI is common in pediatric orthopaedic centers, as affected individuals frequently require orthopaedic care during their growing years. Long bone fracture is common in children with OI. Bone strength assessment is critical in evaluating the effectiveness of current and new preventions and treatments of fractures in OI. Clinical decision-making could be put on a firmer basis if there was a more objective, quantitative way to assess a bone's capacity to withstand loading. The goal of the present project is to develop a micro-FE model of OI bone mini beams and a model to predict strength from clinical bone mineral density data. Very little data is yet available to describe bone material properties in OI. The first characterization studies of OI bone done by our team used nanoindentation to measure elastic moduli at the microstructural scale in small biopsies or surgical specimens of OI bones. Within that scale, the elastic modulus of bone tissues was found to be higher in children with severe OI vs age-matched controls, and to be slightly higher in children with mild vs severe OI. Our team developed a methodology using larger specimens of OI cortical bone. Using this technique, it was found that OI diaphyseal specimens had reduced material strength compared to normal pediatric bone. In addition, our team also imaged bone mini beams using micro-computed tomography (micro-CT). This allowed for the examination of cortical bone porosity. Imaging analyses provide microstructural detail that would otherwise be unknown. This data contributes to our knowledge of bone strength and fracture risk. A more detailed method for assessing bone strength is finite element analysis (FEA), a computational tool widely used in engineering to evaluate stresses and strains (i.e., internal local loading and deformation) within a complex structure by dividing it into smaller, simpler parts (elements). Using patient-specific geometric information and accurate mechanical properties of OI bone, FEA can simulate the behavior of long bones and assess fracture risk. The study PI has previously assessed femur fracture risk in OI by using approximate reconstruction methods to create bowing in the femur along with estimated OI bone tissue properties. This work also showed increased fracture risks with increased bowing as well as increased OI severity. However, this model cannot be validated as that would require knowing the exact force magnitude and location required to break the femur. Developing micro-FE models of the OI bone specimen mini beams will provide the first validation of OI bone strength modeling and answer questions about relationships between microstructure, macrostructure, vBMD, clinical data and whole bone strength.